Dihydroartemisinin (DHA) is an active metabolite of artemisinin. Artemisinin was first identified and extracted from traditional Chinese medicine qinghao (plant Artemisia annua L) in 1972. DHA has been extensively used in the clinic to treat malaria and is well-tolerated by humans and animals. In our preliminary studies, we have found that DHA induces apoptosis in human prostate cancer cells. We have also found that DHA upregulates death receptor 5 (DR5) and cooperates with TRAIL (the ligand for DR5 that has potentially emerged as a novel nontoxic anticancer agent) to induce apoptosis in human prostate cancer cells. Furthermore, DHA strongly inhibits Akt (protein kinase B), which is a key player in transducing survival signals. NKX3.1 is a homeodomain transcription factor and its function is linked to inhibition of prostate carcinogenesis. Our preliminary results also indicate that NKX3.1 upregulates DR5 promoter function. Therefore, we hypothesize that the anti-malarial drug DHA has a significant potential for prevention of prostate cancer. Our preliminary results support our hypothesis and form the basis of this application to further study the molecular mechanisms by which DHA mediates its anticancer effect and to develop this agent as a novel cancer-preventive agent for prostate cancer. We are proposing two specific aims to test our hypothesis. Specific Aim 1 is to investigate the role of homeodomain NKX3.1 transcription factor in mediating DHA-induced upregulation of DR5. Specific Aim 2 is to investigate the prostate cancer preventive effects of DHA in TRAMP and Nkx3.1/Pten mutant mice. These are pilot studies and if successful, will (i) provide important insights into the molecular mechanisms by which DHA mediates its apoptotic and anticancer effects and (ii) lay the groundwork to develop DHA as a novel cancer-preventive agent for prostate cancer.